Archives ofDtsease in Childhood 1993; 68: 97-100 97

Pulmonary veno-occlusive disease: diagnosis during Arch Dis Child: first published as 10.1136/adc.68.1.97 on 1 January 1993. Downloaded from life in four patients

R N Justo, A J Dare, C M Whight, D J Radford

Abstract Case reports Pulmonary veno-occlusive disease is a rare CASE 1 form of primary pulmonary of A seven year old boy presented in 1973 with a unknown aetiology. Four cases were diagnosed four month history of increasingly frequent in young patients. The diagnosis was sus- recurrent episodes of acute dyspnoea, sweating, pected on the basis of clinical, radiological, and abdominal pain. These episodes usually echocardiographic, and catheter evidence and lasted about one hour and settled spontaneously. confirmed by taking a lung biopsy sample. In He had mild asthma as an infant but was all patients the histology showed obstruction without symptoms for the previous three years. of the pulmonary by intimal fibrosis. On clinical examination he was a healthy boy The clinical course of all patients has been without cyanosis who had neither tachycardia one of progressive deterioration. Although nor tachypnoea at rest. He was hypertensive there is no specific treatment for this disease, with a of 150/80 mm Hg. A right to establish the diagnosis during life is of great ventricular heave was present. Cardiac ausculta- importance in overall clinical management, tion showed an accentuated pulmonary com- including counselling the patient and family. ponent of the second heart sound but no murmurs, and normal breath sounds were heard on auscultation of his chest. Chest radio- (Arch Dis Child 1993;68:97-100) graphy showed a normal cardiac outline but pulmonary changes were consistent with acute Pulmonary veno-occlusive disease is an un- pulmonary oedema (fig 1). common disorder characterised by pulmonary Thepatient underwentcardiac catheterisation. hypertension secondary to progressive obstruc- These original records were not available for tion of the pulmonary veins and venules.' review, but the haemodynamic findings were Approximately 100 cases have been reported in interpreted as being 'consistent with a left atrial detail and the clinical diagnosis has not often lesion', whereas angiography showed normal http://adc.bmj.com/ been made during life.2 Four patients with this cardiac anatomy. As a result of these apparent disease who were managed at our hospital inconsistencies, surgical exploration of the right during the past 18 years are presented in and left atria was performed. This showed the chronological order. They were all diagnosed presence of four normal pulmonary veins and during life and illustrate varied presentations, confirmed normal cardiac anatomy. During the use of investigative modalities, and natural operation the pulmonary peak systolic

history. pressure was 50 mm Hg and the mean pulmonary on October 1, 2021 by guest. Protected copyright.

Department of Paediatric , The Prince Charles Hospital, Brisbane, Queensland, Australia R N Justo A J Dare C M Whight D J Radford Correspondence to: Dr D J Radford, Department of Cardiology, The Prince Charles Hospital, Rode Road, Chermside, Figure I (A) Chest radiograph ofcase I taken at the age of8years, showing normal cardiothoracic ratio, prominent main Queensland, Australia 4032. pulmonary artery, and pulmonary oedema. (B) Chest radiograph ofthe same patient taken 15 months later, showing Accepted 13 August 1992 progresstve radiological changes. 98 8Justo, Dare, Whight, Radford

venous pressure was 4 mm Hg. In view of these CASE 3 findings, a lung biopsy sample was taken and An 11 year old girl with dysmorphic features,

the diagnosis of pulmonary veno-occlusive developmental delay, and cardiac abnormalities Arch Dis Child: first published as 10.1136/adc.68.1.97 on 1 January 1993. Downloaded from disease confirmed histologically. was admitted in early 1991 for investigation of He recovered well after the operation but the increasing dyspnoea. She had developed asthma subsequent course of his illness was progressive at the age of 5 years and, apart from intermittent deterioration with intermittent hospital admis- exacerbations of her asthma, remained well sions. He was treated with digoxin, frusemide, until the age of 9 years. At this time she warfarin, and with oxygen at home. This developed exertional dyspnoea which progressed regimen did not significantly alter the course of slowly over the next two years, by which time his illness, however, and he finally died 18 she became dyspnoeic at rest. months after the onset of symptoms. Permission She had congenital heart disease consisting of for a necropsy was refused. coarctation of the , bicuspid aortic valve, and subaortic membrane. The coarctation was originally repaired at the age of 6 months. At CASE 2 the age of 5 years, the coarctation was revised A 17 year old presented in 1979 with an eight and a subaortic membrane was resected. She week history of malaise and progressive exer- also had some dysmorphic features including tional dyspnoea which followed an acute febrile short stature, mid facial hypoplasia, prominant illness. She was referred for further investigation nasal bridge, deep set eyes, small hands, and as she was observed to become cyanosed and clinodactyly of the fifth finger, which had not dyspnoeic after minimal exertion. The only been classified into any syndrome. Chromo- relevant past history was an episode of ence- somal analysis was normal. phalitis following infectious mononucleosis at On examination she was not cyanosed at rest. the age of 9 years. She had not taken any Her respiratory rate was 50 per minute. The drugs. pulmonary component of the second heart Clinically, she was a healthy girl without sound was loud and there was a grade 2/6 resting cyanosis. On palpation there was a right ejection murmur in the pulmonary area. Aus- ventricular heave. Cardiac auscultation showed cultation of the chegt showed fine basal inspira- an accentuated pulmonary second heart sound, tory crackles. The electrocardiogram showed tricuspid regurgitation, and pulmonary regur- sinus rhythm and RSR in lead VI, whereas on gitation. Her breath sounds were vesicular and chest there was mild cardiomegaly, the remainder of the physical examination was bilateral perihilar changes, and diffusely in- normal. The electrocardiograph showed sinus creased reticular markings. rhythm, right atrial, and right ventricular Echocardiography excluded left sided cardiac hypertrophy, and chest radiography showed lesions and pulmonary ostial stenosis as a prominant pulmonary , increased reti- cause for the respiratory symptoms. She had

cular markings, and Kerly B lines, with a had a recent left heart catheter study, but not a http://adc.bmj.com/ normal cardiac outline. right heart study because of venous access Arterial blood gas analysis confirmed the problems. As no important cardiac disease presence ofhypoxaemia (oxygen partial pressure could be shown it was felt that a lung biopsy 52 mm Hg) and respiratory function testing sample should be taken to exclude interstitial showed the presence of a restrictive defect. lung disease. At the operation the right middle Echocardiography showed right ventricular and lower lobes were grossly abnormal with but no hypertrophy other cardiac disease. scarring and reddened discoloration. Pulmonary on October 1, 2021 by guest. Protected copyright. At cardiac catheterisation there was severe veno-occlusive disease was diagnosed histo- pulmonary hypertension (pulmonary artery logically. The findings were typical of the phasic pressure of 65/40 mm Hg with a mean of disease with the small veins affected by 'fluffy' 50 mm Hg) and the pulmonary arterial wedged myxomatous intimal proliferation. There was pressure was 15 mm Hg. Angiography showed no evidence of . dilated pulmonary arteries with normal venous On review nine months later, the child was return to the left atrium, though blood flow in tachypnoeic at rest and becoming increasingly the pulmonary circulation was considered to be tired and dyspnoeic with exertion. She required slow. All other investigations including viral oxygen treatment and drug treatment with serology, rheumatoid factor, and antinuclear frusemide, nifedipine, salbutamol (Ventolin, factors were normal. Allen and Hanburys), and beclomethasone On the basis of this information the diagnosis dipropionate (Becotide, Allen and Hanburys). of pulmonary veno-occlusive disease was sug- gested and an open lung biopsy sample was CASE 4 taken. At the operation the lung appeared A 5 month old baby presented in 1991 with a macroscopically normal, but the histology of two day history of irritability, poor feeding, and tissue from the right middle lobe confirmed the tachypnoea. He had been previously well with diagnosis of pulmonary veno-occlusive disease. no past history of cardiac or respiratory symp- After the operation she was treated with toms, though there have been a history of poor oxygen, a heparin infusion, prednisone, aza- weight gain. thioprine, digoxin, and frusemide (Lasix, The child was peripherally shut down on Hoechst). Her respiratory function deteriorated admission. He had small volume peripheral rapidly despite this treatment and she died three pulses and a right ventricular heave. His heart months after the onset of symptoms. Permission sounds were normal and a soft systolic murmur for necropsy was refused. was audible at the lower right sternal edge. Fine Pulmonary veno-occlusive disease 99

inspiratory crackles were heard throughout both lung fields. He had marked . The electrocardiograph showed sinus rhythm, a normal axis, right atrial hypertrophy, and right Arch Dis Child: first published as 10.1136/adc.68.1.97 on 1 January 1993. Downloaded from ventricular hypertrophy, whereas severe pul- monary oedema with a normal sized heart was seen on chest radiography. Echocardiography showed a grossly dilated hypertrophied right ventricle with flattening of the left ventricle. On Doppler examination there was marked tricuspid regurgitation with a calculated right ventricular systolic pressure of approximately 150 mm Hg. There was no right ventricular outflow tract or pulmonary arterial Figure 3 Histology ofbiopsy samplefrom case 3. obstruction. Careful Doppler interrogation of Pulmonary lobules (L) are separated by widened interlobular the left atrium detected turbulent flow which septa (S) producing a 'jigsawpuzzle' appearance ofthe lung. Septal.lymphatics (arrow)heads) appear dilated could be traced into the pulmonary veins, (haematoxylin and eosin stain x 70). suggesting obstruction within the pulmonary venous tree. After being ventilated he underwent cardiac catheterisation to distinguish between lymphatics and variable haemosiderin accumu- pulmonary vein ostial stenosis and pulmonary lation in the alveolar septa. veno-occlusive disease. The pulmonary artery The first three patients showed fibrosis of pressure was 120/70 mm Hg (mean 95 mm Hg) alveolar and interlobular septa giving a 'jig- and the mean right and left pulmonary arterial saw puzzle' appearance to histological sections wedged pressures were 23 and 17 mm Hg (fig 3). respectively. Directly measured peripheral Cases 1, 2, and 4 showed multiple lumina in pulmonary venous mean pressures measured in small pulmonary veins, suggesting recanalisation different areas of the right and left lungs ranged following organisation ofthrombi. Actual venous from 36 to 46 mm Hg. The left atrial pressure thrombus was only seen in case 4. Small veins in was normal. Angiography by direct injection of case 3 showed 'arterialisation' with twin elastic contrast into pulmonary veins showed multiple lamellae seen on elastin stains. Small pulmonary areas of narrowing within both lungs. The veins arteries were normal in this patient but showed in their extrapulmonary course were angio- grade 1 pulmonary hypertensive changes in the graphically normal. The areas of pulmonary others. venous obstruction so defined corresponded with the sites of marked stasis of antegrade Discussion flow. Pulmonary veno-occlusive disease is a rare form Pulmonary veno-occlusive disease was diag- ofprimary pulmonary hypertension of unknown nosed on the basis of these findings. After aetiology. Approximately 100 cases have been http://adc.bmj.com/ careful discussion of the prognosis of this reported and about one third have occurred in disease with the parents, ventilatory support children with an equal distribution between the was withdrawn and the child died shortly sexes.3 Most patients have been diagnosed at afterwards. Necropsy was performed and this necropsy on typical histological findings. The confirmed the diagnosis of pulmonary veno- disease is now characterised well enough to occlusive disease with multiple acute pulmonary allow an earlier diagnosis. Patients usually infarcts. present with a history of progressive dyspnoea. on October 1, 2021 by guest. Protected copyright. They have signs consistent with pulmonary Histology hypertension, including a right ventricular heave The histopathological changes common to all and a loud pulmonary heart sound. Inspiratory four patients consisted of patchy eccentric crackles which are a result of pulmonary con- myxomatous intimal fibrosis ofsmall pulmonary gestion are often audible on auscultation of the veins (fig 2). There was also dilatation of septal chest. The chest radiographs shows a prominent right ventricle, dilated pulmonary arteries, and Kerly B lines. Electrocardiographic abnor- . : }''$t fi f malities include right axis deviation and right ventricular hypertrophy. Echocardiography will usually show evidence of increased right systolic *V~~~~~~~~~ heart pressure such as right ventricular hyper- trophy or systolic compression of the left ventricle, and will exclude left sided obstructive lesions such as , cor 07,,.,,W. 1 : triatriatum and mitral stenosis. The haemo- et dynamic findings with cardiac catheterisation are pulmonary hypertension with increased right ventricular and pulmonary artery pres- sures. In pulmonary veno-occlusive disease pulmonary capillary wedge pressure has been Figure 2 Histology ofpulmonary veno-occlusive disease in case 1. An irregularproliferation ofintimalfibrous tissue (F) reported to be normal or increased.3 Where partially occludes the lumen ofthis venule (elastin Van there is widespread disease of the pulmonary Greson stain x300). ¢. . 4 '. E A veins, however, the wedge pressure may be 100 0Justo, Dare, Whight, Radford

considerably increased, as in case 4, and selective Regardless of the aetiology, pulmonary veno- direct measurement of pulmonary venous pres- occlusive disease is fatal in most patients within sures will show high intrapulmonary venous two years of the onset of symptoms due to pressures. The left atrial pressure is normal. progressive pulmonary hypertension with right Arch Dis Child: first published as 10.1136/adc.68.1.97 on 1 January 1993. Downloaded from Although this constellation of findings is highly ventricular failure. Treatment with anti- suggestive of pulmonary veno-occlusive disease, coagulants has not been successful'4 but there the definitive diagnosis can be made by taking have been reports of patients responding to an open lung biopsy specimen. The main azathioprine. ' Similarly, there have been diagnostic microscopic feature of pulmonary isolated reports of prolonged survival with the veno-occlusive disease is obstruction of the use of calcium antagonist' and vasodilators such pulmonary veins and venules by intimal fibrosis as prazosin.3 None of the three patients reported consisting of loose myxoid connective tissue, in this paper who received treatment appeared often with intravascular fibrous septa thought to to respond to the treatment. In particular, case 2 result from recanalisation of thrombi.2 4 followed a rapidly progressive course despite Lung histology in cases of primary pulmonary the use of intravenous heparin anticoagulation, hypertension has been classified into three high doses of corticosteroids, and azathioprine. pathological types.5 These are (a) plexogenic Treatment with nifedipine was started in case 3 pulmonary arteriopathy, (b) recurrent pul- but no direct measurement of pulmonary resis- monary thromboemboli, and (c) pulmonary tance was performed to assess the effect. No veno-occlusive disease. The histology described drug treatment was started in case 4 because of in our cases of pulmonary veno-occlusive disease the advanced stage of the disease process. are distinct from the other types. In plexogenic The four cases reported here further show the pulmonary arteriopathy the disease is in the varied clinical course of this disease in children. muscular pulmonary arteries and arterioles with These patients presented over a period of 18 medical hypertrophy and intimal cellular years, and all were diagnosed while still alive. proliferation. In thromboembolic pulmonary As detailed in the case discussion, diagnostic hypertension obstructive lesions of thrombi in methods have evolved with progress in medical various stages of organisation are present in the technology. When investigative information muscular pulmonary arteries and arterioles. indicates obstruction within the lungs, probably These were not the changes seen in our patients. at the level of the pulmonary veins, a lung It is thought that pulmonary veno-occlusive biopsy sample will provide the definitive diag- disease represents a syndrome rather than a nosis. This applied in the first three patients, single aetiological entity, though a common but was not felt to be necessary in case 4 where pathogenesis, probably thrombosis, is likely. It haemodynamic and angiographic data were has been suggested that a primary disturbance conclusive in showing widespread intra- of the vascular wall of pulmonary veins and pulmonary venous disease. Although there has arteries may result in the formation of intra- been no effective treatment for pulmonary vascular thrombi. Various aetiological agents veno-occlusive disease, to establish the diagnosis have been associated with this process. Res- during life is of great importance in overall http://adc.bmj.com/ piratory , usually viral in nature, have clinical management, including counselling the been implicated6 and some workers have shown patient and family. Consideration can now be immune complexes resulting from such infec- given to heart-lung or lung transplantation. tions in the vascular tissue.7 This suggests the I Salzman GA, Rose VW. Prolonged survival in pulmonary possibility of a pathological immune response to veno-occlusive disease treated with nifedipine. Chest 1989; 95:1154-6. a viral . A genetic predisposition has 2 Wagenvoort CA, Wagenvoort N, Takahashi T. Pulmonary been proposed because of case reports of the veno-occlusive disease: involvement of pulmonary arteries on October 1, 2021 by guest. Protected copyright. disease in toxic and review of the literature. Hum Pathol 1985;16:1033-41. occurring siblings.8 9 A aetiology 3 Palevsky HI, Pietra GG, Fishman AP. Pulmonary veno- has been implicated with reports of veno- occlusive disease and its response to vasodilator agents. Am occlusive disease occurring the Rev Respir Dis 1990;142:426-9. following 4 Wagenvoort CA. Pulmonary veno-occlusive disease; entity or administration of chemotherapeutic drugsl' syndrome? Chest 1976;69:82-6. and inhalation of a toxic 5 Edwards WD, Edwards JE. Clinical primary pulmonary substance.'2 hypertension. Three pathologic types. Circulation 1977;56: Cases 1 and 4 had no relevant past history 884-8. 6 McDonnell PJ, Summer WR, Hutchins GM. Pulmonary which would suggest an aetiology for their veno-occlusive disease: morphological changes suggesting a illness. The fact that case 4 occurred at such a viral cause. JAMA 1981;246:667-71. raises the of a 7 Corrin B, Spencer H. Pulmonary veno-occlusion. An immune young age, however, question complex disease? Virchows Arch [Al 1974;364:81. congenital pathological process. The onset of 8 Voordes CG, Kuipers JRG, Elema JD. Familial pulmonary veno-occusive disease: a case report. Thorax 1977;32- pulmonary veno-occlusive disease in case 2 763-6. followed an acute febrile illness and although no 9 Davies PP, Reid L. Pulmonary veno-occlusive disease in siblings: case reports and morphometric study. Hum Pathol organism was isolated, the possibility of a viral 1982;13:91 1-5. infection remains. Case 3 developed this disease 10 Joelson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol 1983;14:88-91. in association with a history of congenital heart 11 Hackman RC, Madtes DK, Clark JG. Pulmonary veno- disease and asthma. The latter was associated occlusive disease following bone marrow transplantation. Transplantation 1989;47:989-92. withgenuineclinical bronchospasm andoccurred 12 Liu L, Sackler JP. A case of pulmonary veno-occlusive intermittently before and after the other diag- disease. Aetiologic and therapeutic appraisal. Angiology 1972;23:299-304. nosis was made. In this instance (and in others) 13 Fong LV, Anderson RH, Zuberbuhler JR. Morphologic it was essential to exclude obstructive lesions of features of stenosis of the pulmonary veins. Am J Cardiol 1988;62:1 136-8. the left heart."' Having clearly done this, an 14 Thadami U, Burrow C, Heath D. Pulmonary veno-occlusive open lung biopsy sample was taken, allowing disease. QJ Med 1975;44:133-59. 15 Sanderson JE, Spro SG, Hendry PT, Turner-Warwick M. A the diagnosis of pulmonary veno-occlusive case of pulmonary veno-occlusive disease responding to disease to be made. treatment with azothioprine. Thorax 1977;32:140-8.